Biliary atresia (BA) is a disease of infants in which the bile ducts are progressively destroyed (reviewed in (7)). If untreated, the disease uniformly progresses to biliary cirrhosis, liver failure, and death within 2 years. The initial treatment for biliary atresia is the hepato-portoenterostomy procedure, in which the biliary remnants are excised and a Roux-en-Y limb of jejunum is placed in contiguity with the exposed liver surface at the porta hepatis. This is successful in ~50% of cases (8-11), but even patients with apparently adequate biliary drainage may experience ongoing hepatic fibrosis and bile duct loss. Ultimately the majority of patients with biliary atresia will require liver transplantation. s a result, biliary atresia is the most common indication for pediatric liver transplantation in the US The diagnosis is often delayed due to a failure to distinguish the disease from physiologic neonatal jaundice. Conversely, the diagnostic work-up of the jaundiced infant is extensive, including blood tests, ultrasonography, nuclear medicine scans, liver biopsy, and intra-operative cholangiogram. The implementation of a sensitive non-invasive test for BA could accelerate the diagnosis, while also sparing children without BA unnecessary and invasive testing. Circulating microRNA is a novel category of biomarker that has never been explored in BA. The preliminary data presented in this proposal demonstrate that circulating microRNAs are specifically elevated in infants with BA in comparison to children with jaundice from other causes.
Aim 1 of this proposal therefore aims to validate the use of microRNAs as non-invasive biomarkers for the diagnosis of BA. Another challenge in the care of children with BA is the prediction of outcome after hepato- portoenterostomy. If children can be identified prior to the development of these outcomes, more aggressive monitoring, nutrition, anticipatory counseling - and perhaps in the future, therapy - can be provided.
Aim 2 of the proposal therefore focuses on testing the ability of circulating miRNA to predict survival with the native liver after hepato-portoenterostomy. The successful implementation of miRNA-based, non-invasive diagnostic and prognostic tests for BA promises to have an immediate and significant impact on children with the disease. It may also lead to insights regarding BA pathogenesis and progress, as well as applications in other liver diseases.

Public Health Relevance

Biliary atresia (BA) is a disease of infants in which the bile ducts linking the liver to the intestine are destroyed. It is the most common reason for a child to need a liver transplant in the US. The goal of this proposal is to develop new non-invasive diagnostic and prognostic tests for BA, so that children can be diagnosed and receive treatment as early as possible, because this has a major effect on whether or not liver transplant will be necessary.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-DKUS-D (80))
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Doo, Edward
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Children's Hospital of Philadelphia
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Zahm, Adam M; Hand, Nicholas J; Boateng, LaTasha A et al. (2012) Circulating microRNA is a biomarker of biliary atresia. J Pediatr Gastroenterol Nutr 55:366-9